Structure-based design of a quadrivalent fusion glycoprotein vaccine for human parainfluenza virus types 1-4

Area of Science:

• Virology
• Immunology
• Vaccine Development

Background:

• Parainfluenza viruses (PIVs) are significant respiratory pathogens, with PIV3 causing severe illness in vulnerable populations.
• Current PIV vaccines are limited, necessitating the development of broadly protective immunogens.
• Stabilizing the prefusion conformation of viral fusion (F) glycoproteins is a strategy to elicit potent neutralizing antibodies.

Purpose of the Study:

• To engineer stabilized prefusion F glycoproteins for all four PIV types (PIV1-4).
• To evaluate the immunogenicity and neutralizing antibody responses elicited by these stabilized prefusion F immunogens.
• To assess the potential for a quadrivalent vaccine strategy against PIVs.

Main Methods:

• Engineered mutations in PIV F glycoproteins to stabilize their prefusion states.
• Determined the cryoelectron microscopy structure of stabilized prefusion PIV3 F bound to an antibody.
• Immunized mice and nonhuman primates (NHPs) with stabilized prefusion F immunogens (monovalent and quadrivalent).
• Assessed neutralizing antibody titers against homologous and heterologous PIV types.

Main Results:

• Stabilized prefusion PIV3 F immunogens induced 200- to 500-fold higher neutralizing titers in mice compared to postfusion F.
• Stabilized prefusion Fs for PIV1, PIV2, and PIV4 showed 2- to 20-fold higher titers than postfusion Fs.
• Quadrivalent immunization in NHPs elicited potent neutralizing responses against all four PIV types.
• NHP responses to stabilized PIV3 F surpassed titers seen in human adults, indicating high immunogenicity.

Conclusions:

• Engineered prefusion-stabilized F glycoproteins are effective immunogens for PIVs.
• A quadrivalent vaccine approach using stabilized prefusion Fs shows promise for broad protection against PIV1-4.
• This strategy elicits potent neutralizing antibodies, potentially leading to improved PIV vaccines.